DETAILED ACTION
Previous Rejections
Applicant’s arguments, filed August 4, 2026, have been fully considered. Rejections and/or objections not reiterated from previous office actions are hereby withdrawn. The following rejections and/or objections are either reiterated or newly applied. They constitute the complete set presently being applied to the instant application.
Information Disclosure Statement
The information disclosure statement (IDS) submitted on August 4, 2026, is in compliance with the provisions of 37 CFR 1.97. Accordingly, the information disclosure statement is being considered by the examiner.
Claim Status
Claims 2, 7, 9, 11, 13, 15, 17 – 18, 20, 24 – 27, 29, 30, 32, and 33 are cancelled.
Claims 34 – 37 are newly added.
Claims 1, 3 – 6, 8, 10, 12, 14, 16, 19, 21 – 23, 28, 31, and 34 – 37 are examined here-in.
Claim Rejections - 35 USC § 103 (New, Necessitated by Amendment)
The following is a quotation of 35 U.S.C. 103 which forms the basis for all obviousness rejections set forth in this Office action:
A patent for a claimed invention may not be obtained, notwithstanding that the claimed invention is not identically disclosed as set forth in section 102, if the differences between the claimed invention and the prior art are such that the claimed invention as a whole would have been obvious before the effective filing date of the claimed invention to a person having ordinary skill in the art to which the claimed invention pertains. Patentability shall not be negated by the manner in which the invention was made.
The factual inquiries for establishing a background for determining obviousness under 35 U.S.C. 103 are summarized as follows:
1. Determining the scope and contents of the prior art.
2. Ascertaining the differences between the prior art and the claims at issue.
3. Resolving the level of ordinary skill in the pertinent art.
4. Considering objective evidence present in the application indicating obviousness or non-obviousness.
Claims 1, 3 – 6, 8, 10, 12, 14, 16, 19, 21 – 23, 28, 31, and 34 – 37 are rejected under 35 U.S.C. 103 as being unpatentable over Horn (US 2015/0196649 A1, of record) in view of Diebold (Diebold, Y. and Calonge, M., “Applications of nanoparticles in ophthalmology” Progress in Retinal and Eye Research 29, 2010, p. 596 – 609).
Horn teaches compositions and methods for treatment of intraocular neovascularization and/or leakage including wet age-related macular degeneration (abstract).
Horn teaches an ophthalmological composition comprising tyrosine kinase inhibitors, surfactants, and solubilizers (paragraph 0021).
Horn teaches tyrosine kinase inhibitors for the treatment of angiogenesis, noting that tyrosine kinase inhibitors can have severe systemic side effects due to high systemic absorption, and notes that there is a need for ophthalmological compositions to deliver tyrosine kinase inhibitors to the intraocular space (paragraphs 0005 – 0006). Horn teaches tyrosine kinase inhibitors include axitinib, cabozantinib, foretinib, regorafenib, ponatinib, motesanib, cediranib, tivozanib, and sorafenib as suitable for the composition (paragraph 0056).
Horn teaches nonionic surfactants suitable for ophthalmic use such as poloxamers, polysorbates, cyclodextrins, and castor oil, among others (paragraph 0059).
Horn teaches carboxymethyl cellulose, methyl cellulose, hydroxymethyl cellulose, polyvinyl alcohols, and polyvinyl pyrrolidone, among others as viscosity enhancers for inclusion in the composition (paragraph 0061).
Horn teaches preservatives including benzalkonium chloride for inclusion in the composition (paragraph 0070).
Horn teaches buffers for adjusting pH such as acetate buffers, citrate buffers, phosphate buffers, and borate buffers for inclusion in the composition for a pH from 4 to 8 (paragraph 0071).
Horn teaches a method of treating intraocular neovascularization, dry macular degeneration, wet age-related macular degeneration, diabetic macular edema, diabetic proliferative retinopathy, or diabetic vitreoretinal traction, among other conditions (paragraphs 0029 – 0030, 0073 - 0084).
Horn does not teach the ophthalmic preparation comprises nanoparticles which have a size in the range of 1 – 100 nm.
Diebold teaches the missing element of Horn.
Diebold teaches that nanoparticles are an attractive tool for ophthalmological drug delivery because nanoparticles show improved topical passage of large, poorly water-soluble drugs, increased contact time of drug with target tissue, and selective delivery to diseased cells (abstract).
Diebold teaches that size is a key aspect that influences biocompatibility of nanoparticles (p. 605 column 2). Diebold teaches that particles with an ultra-small size, 25 nm or less, show improved lymphatic uptake (p. 606 column 2). Diebold teaches that nanoparticles about 20 nm in size are promising for traversing the blood – retina barrier (p. 607 column 1).
The combination of Horn and Diebold’s teachings renders claims 1, 3 – 6, 8, 10, 12, 14, 16, 19, 21 – 23, 28, 31, and 34 – 37 prima facie obvious as combining prior art elements according to known methods to yield predictable results (MPEP 2143(i)(a)). A person of ordinary skill in the art would be motivated to modify Horn’s teachings for an ophthalmic composition to treat conditions such as intraocular neovascularization and/or leakage including wet age-related macular degeneration (abstract) with Diebold’s teachings for nanoparticles as an attractive tool for ophthalmological drug delivery because Diebold teaches nanoparticles show improved topical passage of large, poorly water-soluble drugs, increased contact time of drug with target tissue, and selective delivery to diseased cells (abstract). As such, a person of ordinary skill in the art would expect that modifying Horn’s teachings with Diebold’s would result in an ophthalmic composition for treating intraocular neovascularization that has improved passage of drug to the target site, increased contact time, and selective delivery due to using nanoparticles as drug delivery vehicle. The combination of prior art elements according to known methods to yield predictable results is prima facie obvious according to MPEP 2143(i)(a).
Horn’s teaching for an ophthalmological composition comprising tyrosine kinase inhibitors, surfactants, solubilizers, and viscosity enhancers (abstract, paragraphs 0021, 0061) in combination with Diebold’s teaching for nanoparticles as ophthalmological drug delivery tools (abstract) reads on instant claim 1. In Horn’s example 2, the composition includes 0.02 – 0.8% w/v cabozantinib (which is equal to 0.2 to 8 mg/mL) ; 1 to 10% w/v Span 20; 0.75 to 1.0% w/v carboxymethyl cellulose; and 0.1 to 10% w/v PEG400 (paragraphs 0173 – 0189). Horn’s teaching for 0.02 – 0.8% w/v cabozantinib which is equal to 0.2 to 8 mg /mL, overlaps on the claimed range of 0.05 – 1 mg/mL active pharmaceutical ingredient as recited in claim 1. If Horn’s 0.02 – 0.8% w/v cabozantinib is set to 0.5% w/v and equal to 1 part, then 1 to 10% w/v Span 20 (surfactant) is equal to 2 to 50 parts; 0.75 to 1.0% w/v carboxymethyl cellulose (thickening agent) is equal to 1.5 to 2 parts; and 0.1 to 10% w/v PEG400 (solubilizer) is equal to 0.2 to 50 parts overlapping on the instantly claimed mass ratio amounts (0.5 – 1.5: 20 – 300 : 0.5 – 70 : 10 – 800) of claim 1. Claimed ranges that overlap teachings of the prior art are prima facie obvious according to MPEP 2144.05(i). Notably, the relative amounts in this example are consistent with relative amounts of these ingredients listed in other embodiments and examples throughout the document (paragraphs 0091 – 0230).
In Horn’s example 2, the solvent is water (paragraphs 0173 – 0189), reading on the requirement for a solvent in instant claim 1.
Diebold’s teaching for nanoparticles, where particles with an ultra-small size, 25 nm or less, show improved lymphatic uptake (p. 606 column 2) and particles about 20 nm in size are promising for traversing the blood – retina barrier (p. 607 column 1) reads on the recitation of nanoparticles with a size range of 1 – 100 nm in claim 1. A particle size range of 25 nm or less overlaps on the claimed range of 1 – 100 nm. Claimed ranges that overlap teachings of the prior art are prima facie obvious according to MPEP 2144.05(i). A person of ordinary skill in the art would be motivated to choose particles in a size range of 25 nm or less because Diebold teaches particles in this size range have improved lymphatic uptake (p. 606 column 2).
Horn’s teachings for a composition with tyrosine kinase inhibitor, surfactant, thickening agent, solubilizer, and solvent, in the relative amounts of example 2 (paragraphs 0173 – 0189), overlap on the claimed amounts of 1 part tyrosine kinase inhibitor; 25 – 200 parts surfactant, 1 – 60 parts thickening agent; and 27.5 – 500 part solubilizer as recited in claim 3. (As in the calculations above, Horn’s example 2 has 1 part tyrosine kinase inhibitor, 2 to 50 parts surfactant; 1.5 to 2 parts thickening agent; 0.2 to 50 parts solubilizer.)
Horn’s teaching for tyrosine kinase inhibitors that include axitinib, cabozantinib, foretinib, regorafenib, ponatinib, motesanib, cediranib, tivozanib, and sorafenib as suitable for the composition (paragraph 0056) reads on claim 4.
Horn’s teaching for nonionic surfactants suitable for ophthalmic use such as poloxamers, polysorbates, cyclodextrins, castor oil, and Span 20 (paragraphs 0059 – 0060, 0173 - 0189) reads on instant claims 5, 6, and 35. (For example, poloxamer 188 has an HLB value of 29.)
Horn’s teaching for one or more surfactants at a concentration of 1 to 21% each w/v of the composition (paragraph 0020) reads on the weight ratio of claim 8, of polysorbates and poloxamers in a range from 1 – 5 : 1. For example, polysorbate in the amount of 5% w/v and poloxamer in the amount of 1% w/v is a weight ratio of 5:1, which falls within the claimed range. The selection of a poloxamer and polysorbate from the limited list of nonionic surfactants taught by Horn would be obvious to try, which is prima facie obvious according to MPEP 2143(i)(e).
Horn’s teaching for carboxymethyl cellulose, methyl cellulose, hydroxymethyl cellulose, and hyaluronic acid, among others as viscosity enhancers for inclusion in the composition (paragraph 0061) reads on instant claim 10.
Horn’s teaching of PEG 400 as a lipid solubilizer (paragraphs 0021, 0173 – 0189) reads on instant claims 12 and 14.
Horn’s teaching for polyvinyl pyrrolidone and polyvinyl alcohol for inclusion in the composition, explaining that these compounds are useful for controlling the viscosity of the composition and controlling drug delivery on the eye (paragraphs 0061 – 0062) reads on claim 16. Horn does not explicitly teach an amount for inclusion in the composition, however, it is within the expertise of a person of ordinary skill in the art to determine an appropriate amount via routine experimentation according to MPEP 2144.05(ii)(a). A person of ordinary skill in the art would find guidance in Horn’s teachings for a viscosity between 10 and 100 cps (paragraph 0061) which would give them a reasonable expectation of success for determining the claimed range via routine optimization. (Notably, povidone is another name for polyvinyl pyrrolidone.)
Although Horn does not teach a specific molecular weight range for polyvinyl pyrrolidone, the requirement for 2,500 to 50,000 Daltons in claim 19 is prima facie obvious according to MPEP 2144.05(ii)(a) because it is within the expertise of a person of ordinary skill in the art to determine via routine experimentation. A person of ordinary skill in the art would have a reasonable expectation for arriving at the claimed range because a person of ordinary skill in the art would know that polymer weight can modulate composition thickness, viscosity, or stability, and would choose lower molecular weight polymer (such as 3,500 Daltons) in order to ensure the composition has suitable flowability for application to the eyes.
Horn’s teaching for tonicity adjustors sodium chloride, potassium chloride, mannitol, or glycerin (paragraph 0069), pH adjusting agents such as acetate buffers, citrate buffers, phosphate buffers, and borate buffers (paragraph 0071) and teaching for preservatives such as benzalkonium chloride for inclusion in the composition (paragraph 0070) reads on instant claim 21.
Horn’s teaching that the composition should have a pH from 4 to 8 (paragraph 0071) overlaps on the claimed range of 5 to 8 as recited in claim 22.
Horn’s teaching that the composition is formulated as an ophthalmic solution for the eyes (paragraph 0086) reads on “eye drops” as recited in claim 23.
Horn’s teaching for an ophthalmological composition comprising tyrosine kinase inhibitors, surfactants, and solubilizers for treatment of intraocular neovascularization, dry macular degeneration, wet age-related macular degeneration, diabetic macular edema, diabetic proliferative retinopathy, or diabetic vitreoretinal traction, among other conditions (abstract, paragraphs 0021, 0029 – 0030, 0073 - 0084) reads on instant claims 28 and 31.
Horn’s teaching for 0.02 – 0.8% w/v cabozantinib (paragraphs 0173 – 0189), which is equal to 0.2 to 8 mg /mL, overlaps on the claimed range of 0.1 – 0.5 mg/mL active pharmaceutical ingredient as recited in claim 34.
With regards to instant claims 36 and 37, as discussed above, Horn’s example 2 includes 0.02 – 0.8% w/v cabozantinib (which is equal to 0.2 to 8 mg/mL) ; 1 to 10% w/v Span 20; 0.75 to 1.0% w/v carboxymethyl cellulose; and 0.1 to 10% w/v PEG400 (paragraphs 0173 – 0189). Horn’s teaching for cabozantinib reads on claims 36 and 37 part i.
Although Horn’s example 2 does not specify a mixture of a polysorbate and a poloxamer each having an HLB value of 13 – 29, where the mass ratio of polysorbate to poloxamer is (1 – 5 ): 1, Horn teaches poloxamers, polysorbates, cyclodextrins, castor oil, and Span 20 (paragraphs 0059 – 0060, 0173 – 0189) as nonionic surfactants suitable for ophthalmic use. Furthermore, Horn teaches the inclusion of one or more surfactants at a concentration of 1 to 21% each w/v of the composition (paragraph 0020). From these teachings of nonionic surfactants, a person of ordinary skill in the art could select polysorbate in the amount of 5% w/v and poloxamer in the amount of 1% w/v is a weight ratio of 5:1, which falls within the claimed range recited in claim 36 part ii. The selection of a poloxamer and polysorbate from the limited list of nonionic surfactants taught by Horn would be obvious to try, which is prima facie obvious according to MPEP 2143(i)(e). Polysorbate 188 has an HLB value of 29, reading on claims 36 and 37 part ii.
Horn’s teaching for carboxymethyl cellulose reads on claims 36 and 37 part iii.
Horn’s teaching for PEG 400 reads on claims 36 and 37 part iv.
Horn teaches polyvinyl pyrrolidone for inclusion in the composition to control viscosity and modulate drug delivery to the eye, emphasizing 10 to 100 cps as a suitable viscosity range (paragraphs 0061 – 0062). Although Horn does not teach a specific molecular weight range for polyvinyl pyrrolidone, the requirement for 2,500 to 50,000 Daltons is within the expertise of a person of ordinary skill in the art to determine via routine experimentation. A person of ordinary skill in the art would have a reasonable expectation for arriving at the claimed range because a person of ordinary skill in the art would know that polymer weight can modulate composition thickness, viscosity, or stability, and would choose lower molecular weight polymer (such as 3,500 Daltons) in order to ensure the composition has suitable flowability for application to the eyes. These teachings read on instant claims 36 and 37 part v.
Horn’s teaching the solvent is water reads on claims 36 and 37 part vi.
Horn’s teaching for 0.02 – 0.8% w/v cabozantinib which is equal to 0.2 to 8 mg /mL, overlaps on the claimed range of 0.1 – 0.5 mg/mL active pharmaceutical ingredient as recited in claims 36 and 37 part a.
As in the calculations above, Horn’s example 2 has 1 part tyrosine kinase inhibitor, 2 to 50 parts surfactant; 1.5 to 2 parts thickening agent; 0.2 to 50 parts solubilizer. Which overlaps on the claimed ranges of 1: (25 – 200): (1 – 60) : (27.5 : 500) as recited in claims 36 and 37 part b. Claimed ranges that overlap teachings of the prior art are prima facie obvious according to MPEP 2144.05(i).
Examiner’s Reply to Attorney Arguments Dated August 4, 2026
Applicant argues that Horn’s disclosure of one or more surfactants each at a concentration from 1% to 21% w/v does not teach or suggest the specifically claimed surfactant pair or the (1 – 5): 1 ratio (Remarks page 14). This argument is not persuasive, because as discussed in the body of the rejection above, Horn’s teaching for one or more surfactants at a concentration of 1 to 21% each w/v of the composition (paragraph 0020) reads on the weight ratio of claim 8, of polysorbates and poloxamers in a range from 1 – 5 : 1. For example, polysorbate in the amount of 5% w/v and poloxamer in the amount of 1% w/v is a weight ratio of 5:1, which falls within the claimed range. The selection of a poloxamer and polysorbate from the limited list of nonionic surfactants taught by Horn would be obvious to try, which is prima facie obvious according to MPEP 2143(i)(e). Further, Applicants are reminded that a skilled artisan is not an automaton, but a person having ordinary skill in the art of formulating pharmaceutical compositions, i.e. a synthetic chemist of PhD, and is capable of fitting teachings of multiple prior art documents together like pieces of a puzzle. See MPEP 2141.03. Therefore, a skilled artisan would be highly capable of combining Horn’s teaching for including multiple surfactants to include the claimed components in appropriate amounts.
Applicant argues that Horn is silent to nanoparticles, and therefore does not teach or suggest the new limitation to amended claim 1 (Remarks page 15). Applicant’s amendment necessitated the new grounds of rejection over Horn in view of Diebold. As discussed in the body of the rejection above, Diebold teaches nanoparticles are suitable for ophthalmic preparations (abstract). Diebold teaches that particles with an ultra-small size, 25 nm or less show improved lymphatic uptake (p. 606 column 2) and particles about 20 nm in size are promising for traversing the blood – retina barrier (p. 607 column 1) thus reading on the amended limitation of nanoparticles with a size range of 1 – 100 nm recited in instant claim 1. A particle size range of 25 nm or less overlaps on the claimed range of 1 – 100 nm. Claimed ranges that overlap teachings of the prior art are prima facie obvious according to MPEP 2144.05(i). A person of ordinary skill in the art would be motivated to choose particles in a size range of 25 nm or less because Diebold teaches particles in this size range have improved lymphatic uptake (p. 606 column 2).
Applicant alleges unexpected results, stating “the claimed components, at the specific weight ratios recited in the amended claims, form nanoparticle-comprising ophthalmic preparations that have superior stability, high encapsulation efficiency, and high active pharmaceutical ingredient content in the nanoparticles” (Remarks page 15).
As an initial matter, the Examiner notes that a proper side-by-side comparison to the closest prior art as required by MPEP 716.02(e) does not appear to have been made. Applicant compares examples 1 – 4 and 9 of the instant application with comparative example 1 of the instant application. Applicant alleges that examples 1 – 4 and 9 show unexpected efficacy in delivering API to the posterior segment of the eye compared to comparative example 1. The Examiner disagrees that this comparison is proper because examples 2 – 4 and 9 appear to be loaded with greater amounts of API (6 mg, 15 mg, 4 mg, mg) than comparative example 1 (2.5 mg). Furthermore, components A – D and solution volume differs for each example as well.
Assuming a comparison between example 1 and comparative example 1 is proper as the closest prior art, the concentration of API in the vitreous body of rats was 19.9 +/- 3.2 ng/g for example 1 and 7.87 +/- 2.83 ng/g for comparative example 1. The Examiner disagrees that higher API delivery associated with smaller particle sizes is unexpected in view of Diebold’s teaching that nanoparticles show improved topical passage of large drugs (abstract) and that smaller particle size is associated with greater lymphatic uptake (p. 606 column 2). In other words, Diebold teaches that nanoparticles have improved drug delivery, so the comparison between example 1 and comparative example 1 allegedly illustrating greater concentration of API in the vitreous body of rats is not unexpected.
Finally, and purely arguendo, even if Applicant has in fact shown unexpected results (of which the Examiner is not persuaded at this time), the Examiner notes that Applicant’s alleged showing would encompass example 1, which has a ratio of 1 API : 30 surfactant: 7.2 emulsion stabilizer : 7.2 thickener: 480 solubilizer and particle size of 14.4 nm which does not appear to be “reasonably representative” of the claims in their current scope. See MPEP 716.02(d). Furthermore, the Applicant has allegedly demonstrated “superior stability, high encapsulation efficiency, and high active pharmaceutical ingredient content” associated with nanoparticles in a size range from 1 – 100 nm, however if this is in fact true it would only have been shown for a specific combination of API, surfactant, emulsion stabilizer, thickener, and solubilizer with particle size of 14.4 nm (page 12, Table 1). It is unclear that a composition containing the specific combination of API, surfactant, emulsion stabilizer, thickener, and solubilizer with particle size of 14.4 nm would be reasonably representative of compositions containing other APIs, surfactants, emulsion stabilizers, thickeners, and solubilizers, in varying amounts, and within the particle size range of 1 – 100 nm, thereby falling within the broader scope of what is presently claimed.
Conclusion
Applicant's amendment necessitated the new grounds of rejection presented in this Office action. Accordingly, THIS ACTION IS MADE FINAL. See MPEP § 706.07(a). Applicant is reminded of the extension of time policy as set forth in 37 CFR 1.136(a).
A shortened statutory period for reply to this final action is set to expire THREE MONTHS from the mailing date of this action. In the event a first reply is filed within TWO MONTHS of the mailing date of this final action and the advisory action is not mailed until after the end of the THREE-MONTH shortened statutory period, then the shortened statutory period will expire on the date the advisory action is mailed, and any nonprovisional extension fee (37 CFR 1.17(a)) pursuant to 37 CFR 1.136(a) will be calculated from the mailing date of the advisory action. In no event, however, will the statutory period for reply expire later than SIX MONTHS from the mailing date of this final action.
Correspondence
Any inquiry concerning this communication or earlier communications from the examiner should be directed to Toriana N. Vigil whose telephone number is (571)270-7549. The examiner can normally be reached Monday - Friday 9:00 a.m. - 5:00 p.m. EST.
Examiner interviews are available via telephone, in-person, and video conferencing using a USPTO supplied web-based collaboration tool. To schedule an interview, applicant is encouraged to use the USPTO Automated Interview Request (AIR) at http://www.uspto.gov/interviewpractice.
If attempts to reach the examiner by telephone are unsuccessful, the examiner’s supervisor, Sahana Kaup can be reached at 571-272-6897. The fax phone number for the organization where this application or proceeding is assigned is 571-273-8300.
Information regarding the status of published or unpublished applications may be obtained from Patent Center. Unpublished application information in Patent Center is available to registered users. To file and manage patent submissions in Patent Center, visit: https://patentcenter.uspto.gov. Visit https://www.uspto.gov/patents/apply/patent-center for more information about Patent Center and https://www.uspto.gov/patents/docx for information about filing in DOCX format. For additional questions, contact the Electronic Business Center (EBC) at 866-217-9197 (toll-free). If you would like assistance from a USPTO Customer Service Representative, call 800-786-9199 (IN USA OR CANADA) or 571-272-1000.
/TORIANA N. VIGIL/Examiner, Art Unit 1612
/SAHANA S KAUP/Supervisory Primary Examiner, Art Unit 1612
Prosecution Insights